Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of collagenolytic activity in gingival crevicular fluid (GCF) has revealed the presence of an enzyme capable of fragmenting native 3/4- and 1/4-collagen cleavage products generated by collagenase. An enzyme with similar activity was also identified in media conditioned by fibroblasts from rat periodontal ligament and gingiva, and by rat osteoblastic cells (ROS 17/2.8, 17/2A, 17/2B). In culture, the enzyme was secreted in a latent form that could be activated by organomercurials. For further characterization of this novel enzyme (MMP-V), the osteoblast proteinase was partially purified. ROS 17/2.8 conditioned medium was harvested daily and the 25%-60% sat. ammonium sulfate fraction chromatographed on an AcA 54 gel filtration column. Latent forms of MMP-V (apparent Mr approximately 54 k) and collagenase (Mr approximately 54 k) were resolved from gelatinase (Mr approximately 76 k) and two collagenase inhibitors (Mr approximately 62 k, approximately 36 k). Activated MMP-V degraded native 3/4-collagen fragments from collagen types I and II in a step-wise manner and was active on denatured collagen. MMP-V showed a divalent cation requirement, was active at neutral pH, and was inhibited by collagenase inhibitor and fetal bovine serum, but not by serine, thiol, or carboxyl proteinase inhibitors. These properties indicate that MMP-V is a member of the matrix-degrading, neutral-metalloproteinase family of enzymes which include collagenase, gelatinase, stromelysin, and telopeptidase. The enzyme may function in the degradation of collagen fibrils by cleaving proteinase-resistant 3/4-collagen fragments that are stabilized by association with neighboring collagen molecules.
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PMID:Initial characterization of a neutral metalloproteinase, active on native 3/4-collagen fragments, synthesized by ROS 17/2.8 osteoblastic cells, periodontal fibroblasts, and identified in gingival crevicular fluid. 304 Aug 31

Tissue inhibitor of metalloproteinases (TIMP) from cultured bovine dental pulp inhibits human rheumatoid synovial matrix metalloproteinase 3 (MMP-3) with a stoichiometry of 1:1 on a molar basis. Among the serine proteinases examined, human neutrophil elastase, trypsin and alpha-chymotrypsin destroyed the inhibitory activity of TIMP against MMP-3 by degrading the inhibitor molecule into small fragments. In contrast, the inhibitory activity of TIMP was not significantly reduced by the actions of cathepsin G, pancreatic elastase and plasmin. These data indicate that neutrophils which infiltrate tissues in various inflammatory conditions may play an important role in regulating TIMP activity in vivo through the action of neutrophil elastase.
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PMID:Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinases. 316 16

Using human articular chondrocytes in monolayer culture as an experimental system, we have been studying mechanisms of control of production and activity of neutral proteases which degrade connective tissue matrices. Soluble factors from cultured human blood mononuclear cells (MCF) or synovial fragment cultures (SF) stimulate the production of collagenase and proteoglycanase by chondrocytes. Chondrocytes also release a collagenase inhibitor (mol. wt. 26-31,000), which is similar to the tissue inhibitor of metalloproteinases (TIMP) synthesized by cultured mammalian tissues and this is reduced in cultures exposed to MCF or SF. Retinol and dexamethasone partially inhibit the factor-stimulated collagenase, but increase the amount of inhibitor, restoring it to control levels in the presence of MCF or SF. The effects of these agents in cellular interactions in vitro will be discussed in relation to their possible roles in the control of connective tissue turnover in vivo.
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PMID:Interactions in connective tissues involving monocyte/macrophages and control of production of proteinases and proteinase inhibitors. 629 11

Human articular chondrocytes in culture produced large amounts of specific mammalian collagenase, gelatinase and proteoglycanase when exposed to dialysed supernatant medium derived from cultured human blood mononuclear cells (mononuclear cell factor) or to conditioned medium, partially purified by fractionation with ammonium sulphate (60-90% fraction), from cultures of human synovial tissue (synovial factor). Human chondrocytes and synovial cells also released into culture medium an inhibitor of collagenase of apparent molecular weight about 30 000, which appeared to be similar to the tissue inhibitor of metalloproteinases synthesised by tissues in culture. The amounts of free collagenase inhibitor were reduced in culture media from chondrocytes or synovial cells exposed to mononuclear cell factor or synovial factor. While retinol inhibited the production of collagenase brought about by mononuclear cell factor or synovial factor, it restored the levels of inhibitor, which were reduced in the presence of mononuclear cell factor or synovial factor. Dexamethasone markedly reduced the production of collagenase by synovial cells, while only partially inhibiting factor-stimulated collagenase production by chondrocytes. Addition of puromycin as an inhibitor of protein synthesis reduced the amounts of both collagenase and inhibitor to control or undetectable levels.
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PMID:Effects of retinol and dexamethasone on cytokine-mediated control of metalloproteinases and their inhibitors by human articular chondrocytes and synovial cells in culture. 631 Dec 83

Inhibitors of the mammalian metalloproteinases, collagenase, proteoglycanase and gelatinase were isolated from bovine cartilage (extracts and culture medium) and bovine amniotic fluid and serum. These inhibitors either bind or do not bind to concanavalin-A--Sepharose, with Mr (gel filtration) of about 30 000 and 20 000, respectively. Cartilage and chondrocyte culture media contained only concanavalin-A-binding inhibitors whereas cartilage extracts contained only a non-binding inhibitor: serum and amniotic fluid contained both forms of inhibitory activities. In moist biochemical respects, particularly in their abilities to inhibit metalloproteinases, all of the inhibitors were found to be similar. It is concluded that the forms of the inhibitors that differ in Mr may be closely related to the tissue inhibitor of metalloproteinases (TIMP) previously purified from rabbit and human sources. These findings help to clarify other studies on collagenase inhibitors and support the concept that TIMP-like inhibitors may be important in the control of connective tissue degradation.
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PMID:Metalloproteinase inhibitors from bovine cartilage and body fluids. 632 Nov 74

Periprosthetic osteolysis with or without aseptic loosening is a major clinical problem in total hip arthroplasty. While the macrophage response to prosthetic wear debris and its role in periprosthetic osteolysis has been extensively studied, information regarding other cell types (fibroblasts, osteoblasts) is limited. This study explored the response of fibroblasts to particulate wear debris. Fibroblasts isolated from interfacial membranes of patients with failed total hip replacements and normal synovial tissue, when challenged with small-sized ( < 3 microns) titanium (Ti) particles, responded with significantly enhanced expressions of collagenase, stromelysin and, to a much lesser extent, their tissue inhibitor of metalloproteinases (TIMP). These "regulated" expressions at both mRNA and protein levels were correlated with the size and composition of particles. De novo protein synthesis was required for the regulation of these mRNAs. A similar effect could be induced by the treatment of the cells with particle-free conditioned medium from Ti particle-stimulated fibroblasts. Furthermore, this conditioned medium significantly suppressed the mRNA levels of procollagen alpha 1 (I) and alpha 1 (III) in osteoblast-like MG-63 cells. It is concluded that fibroblasts stimulated with certain particle debris may play an important role in periprosthetic osteolysis by releasing bone-resorbing metalloproteinases and mediator(s) which resulted in suppressed collagen synthesis in osteoblasts.
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PMID:The potential role of fibroblasts in periprosthetic osteolysis: fibroblast response to titanium particles. 750 15

Insulin-like growth factor binding protein-3 (IGFBP-3) is degraded by a cation-dependent protease(s) present in the serum of late gestation rats. Proteolysis of IGFBP-3 results in an increase in IGF-I clearance and possibly in IGF bioavailability. Based on our previous findings that matrix metalloproteinases (MMPs) degrade IGFBP-3 in fibroblast conditioned media, we hypothesized that MMPs might be involved in the degradation of IGFBP-3 by rat pregnancy serum. In the present study, we demonstrate that tissue inhibitor of metalloproteinases (TIMP-1), a specific inhibitor of all MMPs, inhibited significantly the degradation of 125I-rhIGFBP-3 by both rat pregnancy serum and rat placental extracts. Purified human MMPs (principally MMP-1 and MMP-3) degraded IGFBP-3 in solution; MMP-3 produced a pattern of IGFBP-3 degradation products identical in size to the fragments produced by pregnancy serum. Furthermore, the combined addition of antihuman MMP-1 IgG and anti-human MMP-3 IgG to rat pregnancy serum blocked almost completely the degradation of 125I-rhIGFBP-3, suggesting that these two MMPs are the principal MMPs involved in IGFBP-3 degradation in rat pregnancy serum. Together, these data suggest that MMPs function as IGFBP-3-degrading proteases in the serum of late gestational pregnant rats.
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PMID:Proteolysis of insulin-like growth factor binding protein-3 during rat pregnancy: a role for matrix metalloproteinases. 752 35

Studies suggest that the interplay between matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs) is an important mediator of tumour invasion and metastasis. Using immunohistochemistry, 40 specimens of colorectal cancer were examined for the presence of TIMP-1 and the MMPs, stromelysin, gelatinases A and B and interstitial collagenase. Neither enzyme nor TIMP-1 was detected in histologically normal mucosa. Within malignant tissue, stromelysin and gelatinase A were conspicuously absent in tumor cells but were immunolocalized to the extracellular matrix and for gelatinase A also to peritumoural fibroblast-like cells. Gelatinase B was confined to polymorphonuclear leucocytes. Interstitial collagenase was not identified. TIMP-1 was present in only three of the 40 tumours within the malignant stroma. These observations suggest that the mesenchymal elements of colorectal carcinomas, by acting as a source of MMPs and TIMPs, may modulate tumour invasion.
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PMID:The distribution of matrix metalloproteinases and tissue inhibitor of metalloproteinases in colorectal cancer. 755 Dec 59

The ability of stromelysin (SL), fibroblast-type collagenase (FIB-CL) and tissue inhibitor of metalloproteinases (TIMP), to differentiate between healthy, gingivitis and periodontitis sites was investigated. SL and FIB-CL are members of a family of enzymes which are capable of degrading most of the extracellular matrix macromolecules. Extracellular control of these enzymes is performed by TIMP. 40 patients each provided 3 GCF samples from healthy, gingivitis and periodontitis sites. GCF samples were collected by means of sterile paper strips. GCF samples were eluted into 500 microliters of assay buffer and assays for SL, FIB-CL and TIMP were performed by a sandwich ELISA. The mean amounts of SL and TIMP in diseased sites (gingivitis and periodontitis) were significantly higher than the mean amount of these GCF components in healthy sites (MANOVA p values were: 0.006 for SL and 0.001 for TIMP). GCF SL and TIMP differentiated healthy from diseased sites. Both SL and TIMP showed moderate correlation with clinical indices. FIB-CL was detectable in only 20.8% of all sites and did not correlate with disease status.
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PMID:Gingival crevicular stromelysin, collagenase and tissue inhibitor of metalloproteinases levels in healthy and diseased sites. 756 Feb 32

The precursor of matrix metalloproteinase 9 (pro-MMP-9) forms a complex with the tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule, and the N-terminal domain of TIMP-1 in the complex interacts and inhibits active MMPs. We have reported that a catalytic amount of MMP-3 (stromelysin 1) activates pro-MMP-9 (Ogata, Y., Enghild, J. J., and Nagase, H. (1992) J. Biol. Chem. 267, 3581-3584). To activate pro-MMP-9 in the complex, however, an excess molar amount of MMP-3 is required to saturate the TIMP-1 in the complex. The aim of this study was to test the hypothesis that the requirement for excess MMP-3 can be circumvented by specific destruction of TIMP-1 by non-target proteinases. We have tested trypsin, plasmin, cathepsin G, neutrophil elastase, and chymotrypsin as possible inactivators of TIMP-1 and found that neutrophil elastase inactivates TIMP-1 in the complex without significant destruction of pro-MMP-9. Once TIMP-1 is inactivated, pro-MMP-9 can be readily activated by a catalytic amount of MMP-3. These results suggest that neutrophil elastase may participate in the connective tissue destruction at the inflammatory sites not only by its direct action on matrix macromolecules but also by rendering pro-MMP-9 in the pro-MMP-9.TIMP-1 complex activable by MMP-3 as well as activating pro-MMP-3.
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PMID:Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase. 762 55


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